Within the pharmaceutical industry there is an increasing interest in providing products of a higher quality, and a number of guidelines and regulations have been formulated during recent years to establish proper quality measurement, analysis and control.
In addition to improving the processing efficiency and quality there is a general interest in providing processes that are both environmentally safer and also pose a reduced risk to an operator of the process. In particular, in a process to produce for instance tablets from active pharmaceutical ingredients (API) and various excipients in a powdery form may require the operator to wear a protective breathing apparatus, or otherwise personal protective equipment, like gloves or coverall, to prevent excessive exposure to the API and also the excipients. Reduction of the risk of contamination of the surrounding environment as well as exposure of the operator to a pharmaceutical product in a tabletting process was addressed in WO03/020499 (Courtoy), wherein a rotary tablet press was described. However, WO03/020499 does not take fully into account the interest in providing better process control.
Typical manufacturing processes hitherto employed within the pharmaceutical field are of a batch nature. Batch manufacturing processes have a number of advantages and provide satisfactory results within many areas. However, due the increasingly widespread application of regulated criteria for monitoring and controlling in particular pharmaceutical manufacturing processes, and to the general increase in the demands to quality by design, the level of quality of monitoring and control attainable by a batch process is often not sufficient, i.e., due to the fact that settings are fixed. Furthermore, a relatively large buffer volume is required, entailing undesired back-mixing of the material stream. As a consequence, manufacturers' and customers' focus of interest has shifted to continuous processes, in which settings may be varied and are allowed to change within a design space. In order to achieve more production output with a batch process, bigger equipment and bigger buffer volumes, with different process settings to attain the same output, would be required. This is known as the scale-up problem. More output with a continuous process just requires longer running, with the ability to maintain the same settings. Furthermore, there is an increased interest for more robust processing equipment and for the ability to control more incoming variation, while maintaining tablet quality. Special precautions have to be taken in order to ensure traceability in a continuous process, just as the requirements to accuracy and control within the framework of for instance the PAT (Process Analytical Technology) devised by United States Food and Drug Administration (FDA).
Some examples of continuous processes have been devised in the prior art, for instance in EP 0 275 834 A1, in which two or more ingredients are fed into the process line at various feed or inlet points, and the ingredients are mixed, dried and subsequently compacted in a conventional tabletting machine. The process line includes a first mixing unit, a drying unit, a sizing unit and a second mixing unit.
Ideally, the output corresponds to the aggregated input of ingredients at the feed or inlet points, i.e. all of the material is fed to the manufacturing machine in a continuous flow and at a constant rate. Due to a variety of factors, this is not feasible in practice. First, it is under any circumstances almost impossible to adjust the output from the mixing and drying units to provide a just-in-time supply of material to the tabletting machine. Second, the continuous production of tablets of a desired high level of quality requires careful monitoring, controlling and adjustment of process parameters in order to avoid a large rejection number from the tabletting machine. This may lead to accumulation of material along the process line awaiting adjustment of certain process parameters. In turn, this inevitably necessitates the use of intermediate buffer vessels in order to store material upstream of the tablet press.
In a more recent document, WO 2010/128359 (GEA Pharma Systems), a contained module being able to operate by a fully continuous process for the production of tablets is devised. By this design of the tablet production module, all units of the tabletting process may be contained, thus reducing the risk of operator exposure and facilitating operation of the tablet press, as all preparations of the material stream fed to the tablet press are carried out in a contained and controlled manner. The term “contained” is defined by its level of containment according to suitable measurements, and is defined as at least dust-tight.
Common to the above modules and processes is that one or more mixing units are utilized. The term “mixing unit” should in this context be understood in its broadest terms. Thus, the mixing unit refers to a unit operation generally capable of mixing or otherwise processing one, two or more components into a desired form. The mixing unit may thus also be capable of modifying the physical form of dry component(s) processed in the mixing unit, e.g. a feed stream of powder(s) may be converted to a granulate comprising the component(s). The mixing unit may be a granulator for making a granulate from dry powders, such as a granulator to which a granulating liquid is added, or a roller compactor. Further examples include a twin screw blender and a twin screw granulator. Furthermore, the mixing unit may include such equipment as a dryer, a dry blender, a continuous dry blender or the like.
Dispensing or dosing the component(s) to the mixing unit, or to a receiving container upstream of the mixing unit, most often takes place from storage hoppers connected to feeders which in turn supply the mixing unit or receiving container with the desired amount of powder(s) or other component(s). Feeding of powders is carried out by means of screw conveyors according to one of two main solutions: volumetric feeding or gravimetric feeding. In volumetric feeding, material held in a hopper is fed into a process at a constant volume per unit of time, whereas in gravimetric feeding, material is fed into a process at a constant weight per unit of time. The weight is measured by a weighing cell. Gravimetric feeders may operate on the loss-in-weight principle, which provides for more accurate dosing than feeders operating on other principles.
In particular in the processing of pharmaceutical products, accurate dispensing or dosing of the powders involved is vital, and loss-in-weight feeders are traditionally utilized.
One example of prior art concerned with achieving an increased accuracy when feeding powders is EP 290 999 B 1, in which powders are fed from storage hoppers to a weighing hopper and further to a mixing or preparation container.
Many existing loss-in-weight feeders thus function well but are often relatively voluminous and heavy, and require certain conditions with respect to for instance the installation conditions in the production area.
Even with all of the above-mentioned provisions, there is still a need for increasing the quality and operating conditions.
Thus, a need exists to overcome the problems with the prior art systems, designs, and processes as discussed above.